Pharmaceutical agents

ABSTRACT

The invention provides a pharmaceutical composition comprising a particular physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methyl-benzenesulphonamide and polyvinylpyrrolidone. It also provides methods for preparing this physical form, and another physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide useful in the preparation of the first mentioned physical form. The compositions are useful in the treatment of diseases in which leukotrienes are implicated, for example asthma.

This is a continuation of application Ser. No. 08/688,162, filed Jul.29, 1996, abandoned, which is a continuation of application Ser. No.08/474,191 filed Jun. 7, 1995 (now U.S. Pat. No. 5,612,367 issued Mar.18, 1997), which is a continuation of application Ser. No. 08/116,781filed Sep. 3, 1993 (now U.S. Pat. No. 5,482,963 issued Jan. 9, 1996),which is a continuation of application Ser. No. 07/805,421 filed Dec.11, 1991 (now U.S. Pat. No. 5,319,097 issued Jun. 7, 1994).

The present invention relates to pharmaceutical agents. Moreparticularly, it relates to a pharmaceutical composition comprising aparticular physical form of a heterocyclic amide derivative, toprocesses for the preparation of this physical form, and to anotherphysical form of the heterocyclic amide useful in the preparation of thefirst-mentioned physical form.

European patent application publication number EP-A2-0199543 disclosescertain heterocyclic amide derivatives which antagonise thepharmacological actions of one or more of the arachidonic acidmetabolites known as leukotrienes, for example C₄, D₄, and/or E₄, whichare known to be powerful spasmogens (particularly in the lung), toincrease vascular permeability and have been implicated in thepathogenesis of asthma and inflammation (see J. L. Marx, Science, 1982,215, 1380-1383) as well as of endotoxic shock (see J. A. Cook, et al.,J. Pharmacol. Exp. Ther., 1985, 235, 470) and traumatic shock (see C,Denzlinger, et al., Science, 1985, 230, 330). The compounds are thususeful in the treatment of diseases in which leukotrienes are implicatedand in which antagonism of their action is desired. Such diseasesinclude, for example, allergic pulmonary disorders such as asthma, hayfever and allergic rhinitis and certain inflammatory diseases such asbronchitis, ectopic and atopic eczema, psoriasis, as well as vasospasticcardiovascular disease, and endotoxic and traumatic shock conditions.

One of the heterocyclic amide derivatives disclosed in EP-A2-0199543 isN-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide.This compound is described in Example 105 of the patent specification,and will be referred to hereinafter as compound 1.

In recent clinical trials compound 1 has been found to be effective inthe treatment of asthma when administered orally to asthmatic patients.This ability of compound 1 to be effective when administered orally isunusual and highly desirable.

The pharmaceutical composition used in the aforementioned clinicaltrials was not entirely satisfactory, and an improved formulation hasbeen sought. As will be described in more detail hereinbelow, a numberof technical problems needed to be solved in order for such acomposition to be obtained.

Compound 1 has been found to possess relatively poor solubility inwater. There has therefore been a need for a pharmaceutical compositionsuitable for oral administration which comprises compound 1 in the solidstate.

It has been found that compound 1 can be obtained in the solid state asa material having a range of different physical properties, dependingupon the way in which it has been isolated and subsequently treated.This ability has been found to be due to the fact that compound 1 canexist in more than one physical form, at least one of which has poorphysical stability, and which physical forms can be obtained inmixtures. It has also been found that different samples of compound 1 inthe solid state have different bioavailabilities.

It is unattractive to develop a formulation containing a mixture ofphysical forms of a compound that have different bioavailabilities,especially where one is physically unstable, because the effective doseof the compound cannot be properly controlled. There has therefore beena need to find methods for preparing physical forms of compound 1substantially free of other physical forms.

Methods for preparing three physical forms of compound 1 substantiallyfree of other physical forms have been found, and the physical stabilityand bioavailability of these three forms have been investigated. Two ofthese forms, referred to hereinafter as forms B and X, have been foundto be physically stable, but to have relatively poor bioavailability.The third of the three forms, referred to hereinafter as form A, hasbeen found to have relatively good bioavailability. However, it has beenfound that this physical form tends to convert into form B in thepresence of water. This property is disadvantageous for a material whichis intended to be formulated in a solid composition, because granulationinvolves the use of water as an adjuvant in the mixing process. Indeedthe tablets used in the aforementioned clinical trials were prepared bythe vet granulation method from form A, and were found to contain form Bin an amount varying from about 25 to about 30% by weight, based on theweight of compound 1.

There is therefore a need for a pharmaceutical composition suitable fororal administration which comprises compound 1 in one physical form,substantially free of other physical forms, which composition isphysically stable, can be prepared reproducibly and has goodbioavailability.

Surprisingly, it has now been found that pharmaceutical compositionsmeeting these requirements may be obtained by selecting form A as theactive ingredient and polyvinylpyrrolidone as a co-ingredient.

Accordingly the present invention provides a pharmaceutical composition,which comprises, as active ingredient, a physical form ofN-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide(hereinbefore referred to as form A) substantially free of otherphysical forms which physical form has an infra-red spectrum (0.5% inKBr) having sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and550 cm⁻¹, and polyvinylpyrrolidone.

Form A has an X-ray powder diffraction pattern having no discernablepeaks, and is therefore amorphous.

It has been found that compositions according to the invention haveacceptable physical stability, can be prepared reproducibly and havesurprisingly high bioavailability.

Where reference is made in this specification to form A substantiallyfree of other physical forms, it preferably means that at least 90% byweight of the compound 1 present is in that physical form, morepreferably at least 95%, for example at least 96%, 97%, 98% or 99%.

The composition according to the invention may be in any conventionalform suitable for oral administration, for example in the form of atablet, capsule, beadlet or powder. Preferably it is in the form of atablet.

In the composition according to the invention, the active ingredient isconveniently present in an amount of from 1 to 90% by weight, based uponthe total weight of the composition, for example from 10 to 50% byweight.

The polyvinylpyrrolidone is conveniently present in an amount of atleast 1% by weight, based on the total weight of the composition. Itmay, together with the active ingredient, account for the total weightof the composition. However, the composition will more usually furthercomprise at least one pharmaceutically acceptable carrier. For example,the polyvinylpyrrolidone may be present in an amount of from 1 to 20% byweight based on the total weight of the composition, preferably from 2to 6% by weight.

Examples of suitable pharmaceutically acceptable carriers include, forexample, sugar derivatives such as mannitol, lactose, sorbitol, glucose,sucrose, dextrose, fructose and xylitol, and cellulose derivatives suchas microcrystalline cellulose, powdered cellulose andhydroxypropylmethylcellulose. Preferably the composition comprises asugar derivative, especially lactose, and a cellulose derivative,especially microcrystalline cellulose. The amount of sugar derivativepresent may, for example be in the range of from 10 to 30% by weightbased upon the total weight of the composition. The amount of cellulosederivative present may, for example, be in the range of from 25 to 70%by weight, based upon the total weight of the composition.

The composition may further comprise one or more processing adjuvantssuch as disintegrants, for example croscarmellose sodium, sodium starchglycolate and starch, and lubricants, for example magnesium stearate,stearic acid, talc and powdered vegetable stearine. The amount ofdisintegrant present may, for example, be in the range of from 1 to 10%by weight based upon the total weight of the composition. The amount oflubricant present may, for example, be in the range of from 0.25 to 2%by weight, based upon the total weight of the composition.

The composition may be prepared by mixing the ingredients according to aconventional method, for example by a granulation process.

According to another aspect, therefore, the invention provides a processfor preparing a pharmaceutical composition which comprises mixing form Asubstantially free of other physical forms with polyvinylpyrrolidone andwater, and drying the resultant mixture.

The quantity of water used will depend upon the type of pharmaceuticalcomposition required (eg a tablet, capsule, powder or beadlet) and thenature of any other ingredient to be incorporated in the composition.Conveniently the weight ratio of water to form A used will be on therange of from 0.1 to 100:1.

When the composition is in the form of a tablet, the weight of thetablet may conveniently be in the range of from 25 to 500 mg, such asfrom 50 to 250 mg, for example from 100 to 200 mg. The tablet may beuncoated or coated. The coating may be a conventional coating and may beapplied by a conventional method.

According to another aspect, the invention provides methods forpreparing form A substantially free of other physical forms of compound1.

Accordingly, the invention provides a process for preparing form Asubstantially free of other physical forms, which comprises heatinganother physical form ofN-[4-[5-(cyclopentyloxycarbonyl)-amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzene-sulphonamide(hereinbefore referred to as form B) substantially free of othercrystalline forms, which physical form is a monohydrate ofN-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamidewhich is crystalline, has an infra-red spectrum (0.5% in KBr) havingsharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 858 cm⁻¹, andan X-ray powder diffraction pattern having peaks at 2θ=10.0, 11.2, 14.6,19.8 and 23.0°, at a temperature in the range of from 90 to 125° C.under reduced pressure.

The dehydration of form B is preferably conducted at a temperature inthe range of from 115 to 122° C.

The pressure during the dehydration of form B is preferably not morethan 100 mbara, more preferably not more than 50 mbara. For example, thepressure may be in the range of from 5 to 50 mbara.

Form B may be prepared substantially free of other crystalline forms bycrystallisation from hot aqueous acetone. In particular, it may beprepared by dissolving a source of compound 1 in aqueous acetone at anelevated temperature, adding more water, and allowing the resultantmixture to cool. Preferably the water is added rapidly so that thecompound 1 initially separates out as an oil. Material prepared in thisway has been found to afford form A in a particularity high state ofmorphological purity.

The crystalline product may be dried at an elevated temperature, forexample at about 60° C. or below. If it is desired to start from animpure source of compound 1, it has been found advantageous to trituratethis impure source with hot toluene/ethyl acetate prior tocrystallisation.

It will be appreciated that if form B is dried at a high temperature,for example at above 60° C., then some conversion to form A may occur.Material prepared by drying form B at a temperature of about 60° C. orbelow has been found to be substantially free of any other physicalforms of compound 1.

Form B is believed to be novel. The invention therefore also providesform B substantially free of other crystalline forms.

The invention also provides another process for preparing form Asubstantially free of other physical forms of compound 1, whichcomprises rapidly evaporating the solvent from a solution of compound 1.For example, it may be prepared by spray drying a solution of compound1.

The solvent may be any liquid substance capable of dissolving compound 1and of evaporation at a temperature below the melting point of form A.Examples of solvents include ketones, such as acetone, and nitrites suchas acetonitrile, optionally in admixture with water. Aqueous acetone hasbeen found to be a particularity suitable solvent.

The temperature at which the solvent is evaporated should be below themelting point of form A. Conveniently it is below 125° C., preferablybelow 120° C. When using acetone as the solvent, it has been found thata significant amount of crystalline material is obtained if thetemperature is below 100° C. Hence, for example, the temperature atwhich the solvent is evaporated may be in the range of from 100 to 125°C.

The solution of compound 1 is conveniently prepared by dissolving acrystalline form of compound 1, such as form B, in the solvent. Asolution prepared in this way will contain a minimum amount ofnon-volatile impurities.

It will be appreciated from the foregoing that aqueous acetone is aparticularly advantageous solvent for use in the preparation of form Asubstantially free of other physical forms. Indeed it has also beenfound that the organic solvent content of form A produced via form Busing this solution is very low. According to a another aspecttherefore, the invention provides a solution of compound 1 in aqueousacetone. The solution may comprise, for example, from 5 to 15% weight ofcompound 1, preferably from 6 to 13%. The solvent may comprise, forexample, from 3 to 9% by weight of water, preferably from 4 to 8%.

The advantageous nature of the compositions according to the inventionmay be demonstrated by comparing their properties with correspondingcompositions in which form A has been replaced with form B or form X,and with a composition comprising form A which contains nopolyvinylpyrrolidone.

Form X is a physical form of compound 1 which is crystalline, has anX-ray powder diffraction pattern with specific peaks occuring at 2θ=8.1,13.7, 16.4, 20.5 and 23.7° and an infra-red spectrum (0.5% in KBr)having sharp peaks at 3370, 1670, 1525, 1490, 1280, 890, 870 and 550cm⁻¹.

Form X may be prepared substantially free of other physical forms by aprocess which comprises dissolving a source of compound 1 in hot aqueousacetone, reducing the volume of the resultant solution by evaporation,adding toluene and further reducing the volume by evaporation. If it isdesired to employ material which is a relatively impure source ofcompound 1, such material may advantageously be triturated with hottoluene/ethyl acetate prior to the crystallisation step.

Each of the forms A, B and X may conveniently be characterised, forexample, by their X-ray powder diffraction pattern alone, or theirinfra-red pattern alone.

BRIEF DESCRIPTION OF THE DRAWINGS

In this specification, infra-red spectra were determined using a 0.5%dispersion of sample material in a potassium bromide disk over the wavenumber range 4000 to 400 cm⁻¹. Examples of infra-red spectra for each offorms X, A and B are given in FIGS. 1, 2 and 3 hereinafter.

X-ray powder diffraction spectra were determined using 2 g of samplematerial mounted in a Philips standard deep pack holder over thescanning range of 4-40° 2θ counting for 4 seconds per point at 0.02°intervals to produce a trace of spacings against intensity for thisrange. Examples of X-ray powder diffraction spectra for each of forms X,A and B are given in FIGS. 4, 5 and 6 hereinafter.

The melting points of each of the forms A, B and X generally depend upontheir level of purity. Typically, form X has been found to have amelting point of above 190° C., for example about 200° C.; form Abetween 115 and 140° C., for example about 124 to 132° C.; and form Babout 140 to 160° C., for example from 145 to 155° C. Form B has beenobserved to lose water at a temperature above about 60° C., and may notshow a sharp melting point.

As stated hereinabove, form A is acceptably stable in the compositionsaccording to the invention. However, under conditions of high relativehumidity and elevated temperatures, conversion of form A into form B hasbeen found to occur. Accordingly, it may in certain circumstances bedesirable to keep pharmaceutical formulations comprising form A in thepresence of a suitable desiccant, such as silica gel. It may also bedesirable to keep them in an airtight container, such as a blister pack.

The dose of compound 1 to be administered to a patient in a compositionaccording to the invention will depend upon the severity of thecondition to be treated, the age and the size of the patient. Ingeneral, the compound will be administered in a dose in the range offrom 0.1 to 10 mg/kg, for example from 0.2 to 5 mg/kg.

Acute toxicity studies have been conducted on compound 1 in order toobtain LD₅₀ values. For example, in mice and rats it has been found thatthe LD₅₀ value for compound 1 is >500 mg/kg.

The following non-limiting Examples illustrate the invention.

EXAMPLE 1 Preparation of Form A

a) Preparation of an impure source of compound 1

Methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)-benzoate (preparedas described in Example 4 of EP-A2-0199543) was converted into the freeacid by treatment with aqueous sodium hydroxide. The free acid was thenconverted into the acid chloride by treatment with thionyl chloride indichloromethane. The acid chloride was then reacted witho-toluenesulphonamide in dichloromethane in the presence of 2.2equivalents of 4-dimethylaminopyridine to afford thedimethylaminopyridine salt of4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoyl-2-methylbenzenesulphonamide.

A solution of the dimethylaminopyridine salt of4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoyl-2-methylbenzene-sulphonamide(30 g) in 2-methoxyethanol (130 ml) and concentrated sodium hydroxideliquor (3.2 ml) was charged to a nitrogen-purged flask containing 10%palladium on charcoal (3.3 g of a 60.9% water-wet paste). The mixturewas then stirred under a hydrogen atmosphere at a pressure of 3 bar for2.5 hours. The mixture was then filtered through diatomaceous earth, andwashed through with 2-methoxyethanol (37.5 ml). To the combined liquorswas added cyclopentyl chloroformate (9.2 ml), and the mixture allowed tostir under an atmosphere of nitrogen overnight. The temperature was thenadjusted to 30-33° C., and 0.8 M hydrochloric acid (68 ml) was addedover 20 minutes with vigorous agitation. The mixture was then cooled to15-20° C. and stirred for one hour. The crude crystalline product wasthen filtered off, washed with water and dried at 50° C. It was thenused in the next step.

b) Trituration of impure compound 1

60 g (0.101 gmol) of the product of step a), toluene 240 ml (4 volumes)and ethyl acetate 150 ml (2.5 volumes) were slowly heated to reflux and30 ml (0.5 volumes) of distillate were collected to remove most of thereleased water. The mixture was heated under reflux for one hour (88-90°C.) and was then cooled to 10-15° C. After stirring for three hours at10-15° C., the solid was filtered through a glass sinter and washed witha 2:1 mixture of toluene (80 ml) and ethyl acetate (40 ml). The productwas then dried to constant weight on the sinter to afford 53.2 g of drycompound 1 (yield 91.5%).

c) Preparation of Form B

30.0 g of the product of step b), 210 ml acetone and 12 ml water werecharged to a 500 ml reaction flask. The mixture was then heated underreflux for 15 minutes, and was then screened at 45-50° C. through adiatomaceous earth pad on a glass sinter directly into a 500 ml reactionflask. The flask and sinter were washed with a mixture of acetone (60ml) and water (3 ml). The combined liquids were then stirred in a waterbath at approximately 40° C. and water (120 ml) was added over fiveminutes. The mixture oiled out at first, but then rapidly crystallised.The mixture was then cooled to 20° C. over one hour, stirred for twohours at 15-20° C. and then filtered. The product was washed with water(60 ml), dried as far as possible on the sinter and then dried in an airoven at 60° C. (max.). The yield of form B was 30.0 g (97%).

d) Preparation of Form A

The product of step c) (15.0 g) was placed in a 500 ml round bottomedflask which was then evacuated on a rotary evaporator at 20 mbar. Theflask and contents were then immersed in an oil bath preheated to 118°C., and slowly rotated at this temperature for 6 hours. The mass wasbroken up on cooling to afford form A as a white powder.

For large scale preparations, form A may be prepared as follows:

30 kg of the product of step c) is spread evenly onto metal trays andheated at 120° C. under vacuum in 7 m² vacuum oven for up to 24 hours.Typically the pressure is about 20 mbara. On cooling (to 40° C. orbelow), the material is discharged from the oven and milled to affordthe desired form A.

If desired, the form A may be micronised prior to use.

Preparation of Form X

The product of step b) (30.0 g, 0.0521 gmol) was dissolved in acetone(150 ml) and water (4.7 ml) by gentle heating to reflux, and thesolution screened through a sintered glass funnel. The filtrate washeated to boiling and 90 ml distillate collected. Toluene (120 ml) wasadded and a further 75 ml distillate collected. More toluene (120 ml)was added and an additional 75 ml distillate collected. After heatingfor a further hour at reflux, the mixture was cooled to 15-20° C., andthe product collected and washed with toluene (2×30 ml). The yield afterdrying on the sinter funnel was 29.5 g (98.3%).

EXAMPLE 2 Alternative Preparation of Form A

Form B (which may be obtained as described in Example 1) was dissolvedin aqueous acetone to produce an 8% w/w solution of compound 1 in 6% w/waqueous acetone. This solution was then spray dried using a NiroLaboratory Minor spray drier (obtainable from A/S Niro Atomizer,Gladsaxevej 305, DK-2860 Soeborg, Denmark). The solution was atomised ata flow rate of 2 kg/h with nitrogen at a flow rate of 6.6 kg/h using atwo fluid nozzle atomiser. The drying gas used was nitrogen with a flowrate of 70 kg/h and inlet/outlet temperatures respectively of 215/120°C. The form A produced was collected on a bag filter.

EXAMPLE

    ______________________________________                                        Tablet formulation of Form A                                                               mg/tablet                                                                             mg/tablet mg/tablet                                      ______________________________________                                        Granulating Material                                                          Active ingredient                                                                            2         20        50                                         Croscarmellose sodium NF                                                                     6          5         5                                         Polyvinylpyrrolidone USP                                                                     7          4         8                                         Microcrystalline cellulose NF                                                                54        74        40                                         Lactose NF     54        50        40                                         Purified Water USP                                                                           80        98        62                                         Final Blend Material                                                          Dried milled granulation                                                                     123       153       143                                        Lactose NF     --        20        --                                         Croscarmellose sodium NF                                                                     6          5         7                                         Microcrystalline cellulose NF                                                                69        20        48                                         Magnesium stearate NF                                                                        2          2         2                                         ______________________________________                                    

The ingredients of the granulating material were wet granulated. Thegranules were then dried and milled. The dried milled granulation wasthen blended with the other ingredients of the final blend mixture andcompressed into tablets.

The percentage by weight of form B present, based upon the weight ofcompound 1 present, was determined by X-ray analysis. For the 20 mgtablet, this was found to be <8%. For the 50 mg tablet more sensitiveX-ray methods were used. The percentage by weight of form B beforeformulation was found to be 3%, and after formulation was found to be<3.2%.

Note: In each of the examples herein, the polyvinylpyrrolidone used hada K value of 29-32. It is believed that any pharmaceutical gradepolyvinylpyrrolidone, for example, that having a K value in the range 10to 100, will be suitable.

EXAMPLE 4 Short Term Stability Test

Tablets prepared according to the method of Example 3 and containing 20mg of form A were stored under various conditions for 1, 2 and 3 months.The tablets were then studied by X-ray diffraction to determine how muchof the active ingredient had been converted into form B. The results aresummarised in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        Stability tests on tablet formulation containing form A                       Storage conditions                                                                             % conversion to form B                                       ______________________________________                                        initial          none detectable                                              1 month, room temp.                                                                            none detectable                                              2 months, room temp.                                                                           none detectable                                              3 months, room temp.                                                                           none detectable                                              3 months, 50° C.                                                                        none detectable                                              1 month, 40° C., 80% RH                                                                 87                                                           2 months, 40° C., 80% RH                                                                91                                                           3 months, 40° C., 80% RH                                                                82                                                           ______________________________________                                         RH = relative humidity                                                   

The tablets stored at room temperature and 50° C. were in white highdensity polyethylene bottles with metal caps.

The tablets stored at 80% RH were exposed to the air.

COMPARATIVE EXAMPLE

    ______________________________________                                        Tablet formulation of form A containing no polyvinylpyrrolidone                                mg/tablet                                                    ______________________________________                                        Granulating Material                                                          Active ingredient  50.0                                                       Pregelatinised starch NF                                                                         20.0                                                       Lactose NF         34.55                                                      Sodium starch glycolate NF                                                                       2.0                                                        Microcrystalline cellulose NF                                                                    34.95                                                      Sodium lauryl sulphate NF                                                                        0.5                                                        Purified water USP 100.0                                                      Final Blend Material                                                          Dried milled granulation                                                                         142.0                                                      Sodium starch glycolate NF                                                                       6.0                                                        Microcrystalline cellulose NF                                                                    50.0                                                       Magnesium stearate NF                                                                            2.0                                                        ______________________________________                                    

The ingredients of the granulating material were wet granulated. Thegranules were then dried and milled. The dried milled granulation wasthen blended with the other ingredients of the final blend mixture andcompressed into tablets.

The percentage of compound 1 present as form B was determined by X-rayanalysis before and after granulation. Before granulation it was foundthat <1.5% of the compound 1 was present as form B. However, aftergranulation 28% of the compound 1 was found to be present as form B.

These results clearly demonstrate the improved stability of form A inthe compositions according to the invention.

EXAMPLE

    ______________________________________                                        Capsule Formulation                                                                              mg/capsule                                                 ______________________________________                                        Active Ingredient  20                                                         Polyvinylpyrrolidone                                                                             20                                                         Lactose            177.25                                                     Microcrystalline cellulose                                                                       177.25                                                     Colloidal silicon dioxide                                                                        0.5                                                        Magnesium stearate 5                                                          Size 0 gelatin Capsule                                                        ______________________________________                                    

Mix the active ingredient, polyvinylpyrrolidone, lactose andmicrocrystalline cellulose in a suitable mixer, mix with purified waterto proper consistency, dry, size through a suitable milling operation.Mix with the colloidal silicon dioxide and magnesium stearateEncapsulate with size 0 two piece gelatin capules.

    ______________________________________                                        Beadlets (spheroids)                                                                           mg/capsule                                                   ______________________________________                                        Active ingredient                                                                              10                                                           sugar spheres    200                                                          Polyvinylpyrrolidone                                                                           10                                                           ______________________________________                                    

Prepare a 10% dispersion of the polyvinylpyrrolidone in purified water.Add the active ingredient and mix until uniformly dispersed; spray ontothe sugar spheres using suitable equipment. The beadlets can be filledinto size 1 two piece capsules or dispensed in a suitable sachet.

    ______________________________________                                        Powder Formulation                                                                             mg/powder                                                    ______________________________________                                        Active Ingredient                                                                              20                                                           Polyvinylpyrrolidone                                                                           15                                                           Mannitol         364.6                                                        Flavour          0.4                                                          ______________________________________                                    

Mix the active ingredient, polyvinylpyrrolidone and mannitol in asuitable mixer. Mix to a suitable consistency with purified water, dry,and pass through a suitable sizeing operation.

COMPARATIVE EXAMPLE 2

Comparison of the bioavailability of compound 1 in compositions preparedfrom form A with and without polyvinylpyrrolidone.

24 healthy male human volunteers were randomly assigned to treatmentgroups. One treatment was a single 50 mg tablet prepared as described inExample 3, and another a single 50 mg tablet prepared as described inComparative Example 1. During the course of the study each volunteerreceived both preparations. During each treatment period, blood sampleswere periodically obtained and the concentration of compound 1 wasdetermined.

    ______________________________________                                                                Product of                                                         Product of Comparative                                                        Example 3  Example 1                                                          Mean  standard Mean    standard                                               figure                                                                              enor (I) figure  enor (I)                                  ______________________________________                                        Maximum concentration                                                                        588     54       223   28                                      of compound 1 (ng/mL)                                                         Time to maximum                                                                              2.6     0.3      3.7   0.3                                     concentration (hours)                                                         Half-life      9.0     0.5      8.2   0.7                                     Area under the 2268    220      970   126                                     curve                                                                         (ng · h/mL)                                                          ______________________________________                                    

These results clearly demonstrate the improved bioavailability ofcompound 1 in the compositions according to the invention.

COMPARISON EXAMPLE 3

Comparison of the bioavailability of compound 1 in compositions preparedwith polyvinylpyrrolidone and forms A, B and X.

Tablets containing 20 mg form A, form B or form X were preparedaccording to the following recipee.

    ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Granulating material                                                          Active Ingredient   20                                                        Croscarmellose sodium NF                                                                           6                                                        Polyvinylpyrrolidone USP                                                                           7                                                        Microcrystalline Cellulose NF                                                                     45                                                        Lactose NF          45                                                        Final Blend Material                                                          Croscarmellose sodium NF                                                                           6                                                        Microcrystalline Cellulose NF                                                                     69                                                        Magnesium stearate NF                                                                              2                                                        ______________________________________                                    

Using a balanced crossover design, 8 dogs each received each of thethree tablet forms. During each study period, blood samples wereperiodically obtained from each animal and the concentration of compound1 determined. The results are summarised below.

    ______________________________________                                                  Maximum                                                                       concentration                                                                              Half-life                                                                              Area under curve                              Active ingredient                                                                       (μg/ml)   (hours)  (μg · h/mL)                       ______________________________________                                        Form A    1.004        5.398    4.028                                         Form B    0.105        3.524    0.773                                         Form X    0.314        3.590    1.307                                         ______________________________________                                    

These results clearly demonstrate the superior bioavailability ofcompositions according to the invention, compared with compositionscontaining form B or form X.

What we claim is:
 1. A process for the preparation of a pharmaceuticalcomposition which comprises, as active ingredient, a physical form ofN-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamidesubstantially free of other physical forms, which physical form has aninfra-red spectrum (0.5% in KBr) having sharp peaks at 1690, 1530, 1490,1420, 1155, 1060, 862 and 550 cm⁻¹, and polyvinylpyrrolidone, whichprocess comprises mixing said active ingredient withpolyvinylpyrrolidone and water, and drying the resultant mixture.